Wireless neural stimulator with injectable

ABSTRACT

Neural stimulator systems with an external magnetic coil to produce changing magnetic fields is applied outside the body, in conjunction with one or more tiny injectable objects that concentrates the induced electric field to a highly-targeted location. These systems include a driver circuit for the magnetic coil that allows for high voltage and fast pulses in the coil, while requiring low-voltage power supply that may be powered by a wearable or portable external device, along with the coil and driver circuit.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/342,508, filed Apr. 16, 2019, which is a U.S. National Stageapplication of PCT Application No. PCT/US17/56795, filed Oct. 16, 2017,which claims the benefit of priority to U.S. Provisional PatentApplication Ser. No. 62/408,793, filed on Oct. 16, 2016, U.S.Provisional Patent Application Ser. No. 62/454,842, filed on Feb. 5,2017, and U.S. Provisional Patent Application Ser. No. 62/561,821, filedon Sep. 22, 2017, each of which is hereby incorporated by reference inits entirety.

BACKGROUND

The human and mammal bodies use electrical signals to achieve sensoryinput, muscle movements, thoughts, and memory. Over time, these signalsare also responsible for neural plasticity, which includes generalwiring, rewiring, and de-wiring of the brain. The electrical signals arerepresented in the mind and body as potentials (voltages) created byions, not electrons. However, these ion-transported signals can beinitiated, negated, or altered by electric fields that originate fromoutside the body. By Faraday's law of electromagnetics, these electricfields can be generated from changing magnetic fields, hence, the name“magnetic stimulation”. Because these signals are initiated from outsidethe body, magnetic stimulation can be a non-invasive means for alteringor improving of almost all bodily and mental functions.

The signals inside the body are “action potentials” that arepulse-frequency modulated, meaning that the pulse rate is related to theintensity of the sensed input, muscular energy, or neuronal message. Theshapes of individual pulses are largely the same throughout, having apulse width of about 1 millisecond and some undershoot after the mainpulse. The pulse height is approximately 70 millivolts for sensorysignals and somewhat larger for muscle activation. Pulses for the heart,digestive system, and may other organs have other uniquecharacteristics. For the most part, the signals all look the similarwhen viewed on an oscilloscope: a “pulse train” wherein the pulserepetition frequency is indicative of the magnitude of the transmittedsignal. The absence of a pulse train can also cause a reaction,explaining why amputees still feel parts of the body that no longerexist.

The meaning of the individual signal to the body's nervous system isdependent on where pulse train appears. The brain consists of regionsthat handle various neural functions and provide input for thoughtfuland sensory processing. The peripheral nervous system contains axonsthat serve as communication channels and repeaters between the sensorynerve endings and the spinal cord and ultimately the brain. Theneuromuscular system also consists of axons that communicate in theopposite direction allowing the brain to cause various muscle motions.Axons are grouped together into multi-channel peripheral nerves as theyapproach the spinal cord or the brain. Some axons are myelinated toincrease the propagation rate of the pulse trains to and from theextremities of the body.

Neuromodulation devices strive to create, negate, or alter thesenaturally-occurring pulse trains in a targeted location to achieve abeneficial result. This may include blocking or stimulation of neuralactivity. Ultimately, an electric field is required at the location thatcauses ions to appropriately to trigger an action potential that thencan propagate unassisted through the nervous system to its destination.This electric field may be induced rather than generated directly. Forexample, traditional magnetic stimulation first creates a time-varyingmagnetic field from a coil of wire, which in turn generates an electricfield per Faraday's law. When this electric field is induced on aportion of the neurosensory system, or the neuromuscular system, orbrain's neural network, it can alter that system by depolarizing orhyper-polarizing the pulse trains that naturally exist or by inserting apulse train that does not exist. In the nervous system and the brain,these pulse trains run continuously; only the frequency changes toconvey the intensity information.

The prior-art neural stimulation devices fall into three categories: (1)implanted wire stimulation wherein electrodes implanted at a targetedlocation and connected by wires to a driver circuit possibly alsoimplanted in another part of the body, (2) magnetic stimulation whereinchanging magnetic fields produced by a coil outside the body generateelectric fields inside the body that alters the natural nerve orneuronal signals, and (3) skin-electrode stimulation wherein electrodesare placed on the skin and cause current to flow into the body from oneelectrode to the other. Deep Brain Stimulation (DBS) is an example ofimplanted wire stimulation. Transcranial Magnetic Stimulation (TMS) isan example of magnetic stimulation. Transcutaneous Electrical NeuralStimulation (TENS) and Electro Convulsive Therapy (ECT) are examples ofskin-electrode stimulation.

Implanted wire stimulation is highly targeted, but also highly invasiveand unstable due to electrode movement from wire-tugging during bodilymotions. Infection is also a disadvantage especially if the drivercircuit is not implanted. The mechanism of action is increasing ordecreasing the frequency of natural action potentials and therefore wellunderstood. Examples of implanted wire stimulators include the Vagusnerve stimulator offered by Cyberonics and covered in U.S. Pat. No.8,571,654B2 that has helical electrodes, and US2016/0175600A1 where theimplant includes a battery charged wirelessly by external coilstransmitting the recharge energy magnetically. Some implanted wirestimulators have implanted micro-coils that induce electric fields inthe body instead of providing voltages on electrodes, such asUS2015/0080637.

Magnetic stimulation is non-invasive, but unpredictable and low inefficacy because the stimulation is not targeted and the mechanism ofaction is not understood. Regarding medical treatment, magneticstimulation has achieved regulatory approval for treating majordepression, neuropathic pain, and headaches. According toclinicaltrials.gov, 1165 clinical studies have been or are beingperformed with “magnetic stimulation” by 427 unique sponsors tounderstand its effect on 450 different conditions. Magnetic stimulationmay include a single external coil, multiple external coils for bettertargeting such as US2012/0302821A1 and also wearable coils such as U.S.Pat. No. 9,072,891B1 and US2010/0160712A1.

Skin-electrode stimulation is non-invasive, but untargeted anduncontrollable because the electrical current follows multiple pathswith varying intensity. The mechanism of action of skin-electrodestimulation is not understood except for ECT where an electrical jolt islarge enough to intentionally produce a full seizure in the brain. ECTand TENS are approved for very few indications and efficacy is low.

SUMMARY

The number of approved treatments are minimal today and the efficaciesare very low despite decades of costly research for general magneticstimulation. Many research papers blame the lackluster progress onlimitations of the state-of-the-art apparatus for magnetic stimulation,including the following: (1) lack of targeting of stimulation location(2) premature over-heating of the coils, (3) inability to penetrate deepinto the body, (4) loud noises disturbing the patient, (5) inability topre-test on small animals because small coils overheat very quickly, and(6) inability to define a credible placebo process.

The effect of the prior-art magnetic stimulators when applied to thebrain is called a “virtual lesion” in the sense that all thesestimulators can do is temporarily disable a portion of the brain'scommunication system. Interruption of a patient's speaking is anoften-demonstrated manifestation of the virtual lesion via magneticstimulation. Because the prior art is not able to precisely create thenatural pulse trains that the mind or body expects, the effect ofstimulation is not predictable and often not repeatable. The stimulationintensity is limited by the prior art to a transient and narrow rangebetween no-effect and damaging-effect. What is really needed is a lowerbut continuous intensity, but the overheating of the prior-artstimulators prevents this type of protocol.

The first problem with the prior art magnetic stimulation coils is thatthey overheat prematurely. But, to maintain the expected and predictableresponse, the stimulation must occur continuously. Magnetic stimulatorsof the prior art are limited to a few seconds of stimulation followed bya long and necessary period of cooling down of the coil. If theelectrical current in the prior-art coils was reduced to preventoverheating, the induced pulse trains would be too weak to have aneffect. For this reason, the prior-art systems are over-driven for shortperiods of time between coil cool-downs.

Because of the overheating problem, the devices on the market configuredto automatically turn off when the heat limit is reached. For example, astimulator may require 20-60 seconds of cool-down for every 2-10 secondsof stimulation. In addition, this researcher showed directionally thatmore sessions led to greater remission rates of depression. Continuousand appropriate intensity levels of stimulation, along with bettertargeting, is likely to be far superior to the interruption constraintsof the prior art stimulators.

A second problem with prior art magnetic stimulation is that inducing anelectric field strong enough to evoke an action potential even a fewcentimeters away from a coil is not trivial. The prior-art coils musthave thousands of amperes of electrical current that appears anddisappears in about 100 microseconds, which is the rise time of anaction potential. The coils have inductance, which further requires ahigh-voltage power supply to change the current quickly. This supply isconnected to the coil for about 100 microseconds, and then isdisconnected abruptly. The high voltage is required to change thecurrent in coil quickly, and the high amperes in the coil are requiredto induce a sufficient electric field in the body that achieves oralters an action potential.

For example, the coils in the apparatus available from MAGSTIM, INC.(Morrisville, N.C.) need 5000 amps of current to appear and disappearfrom the coil in about 100 microseconds. In order to achieve this, apower supply of thousands of volts is used. In order for this system tocreate a continuous pulse train requires kilowatts of power, which willeasily overheat the coil and the electronics that drives the coil.

The following patents or patent applications use this method ofswitching on a high voltage power supply to a coil, then switching itoff before the coil overheats in order to allow it to cool down:US20080306326A1, U.S. Pat. No. 6,179,770B1, US20120108883A1, U.S. Pat.No. 6,527,695B1, U.S. Pat. No. 5,743,844A US20070293916A1, and U.S. Pat.No. 8,545,378B2. In these prior patents and patent applications, acapacitor is charged to a very high voltage, then a transistor connectsthis high voltage to the coil briefly to create a magnetic pulse, whichby Faraday's law, induces an electric field pulse in the body. Thetransistor repeats this operation to create multiple pulses, then staysoff to let the coil cool down.

These prior art coil-driver circuits either make no attempt to recyclethe magnetic energy of the coil or merely do so by allowing it to flowback into the high-voltage capacitor, such as described inUS20090018384A1.

The huge amount of current flowing in and out of the prior-art magneticstimulator causes a knocking noise that is loud enough to seriouslydisturb a patient. The coil acts like the voice coil in a speaker,thereby creating sounds from the pulsed magnetic forces acting on thecoil itself or any ferromagnetic materials nearby.

The prior art magnetic stimulator also renders impossible a placebocontrol group because the noise generated allows the human subjects todistinguish the true treatment from the silent or quieter “sham”treatment.

A third problem with the prior art magnetic stimulator is that they donot scale down well to smaller coils for small-animal testing becausethe smaller coils overheat faster than the larger coils designed forhumans. Hence, animal testing is very difficult.

A fourth problem with prior art magnetic stimulators is that theyrequire thousands of volts and thousands of amperes to create a pulsetrain for a too-short period of time and already. Even then, the actionpotentials can only be produced about 1-2 centimeters into the body fora short period of time. Penetrating deeper into the body would requirelarger coils with higher inductance, and hence even higher voltagesand/or current. This severe power requirement has limited magneticstimulation to nerves, axons, and neurons close to the surface of thebody.

Clearly, then, improvements are needed in prior-art magnetic stimulatorsfor magnetic stimulation to become a viable, predictable, pervasive,efficacious, and cost-effective mechanism for health care and forresearch.

The invention described herein addresses all mentioned limitations ofprior-art magnetic stimulation, skin-electrode stimulation, andimplanted wire stimulation. Hence, this invention is expected to greatlyadvance the state of the art of magnetic stimulation for the benefit ofmankind.

In one embodiment, a wireless neuromodulation system is provided toallow wireless stimulation to (1) be targeted to an area as small as asingle node on a neural pathway or a single neuron in the brain, (2)work with readily available power supply voltages, (3) work with largerand smaller stimulating coils in order to reach deeper into the humanbody and to enable small-animal studies, respectively, (4) be wearableand powered with small batteries, (5) dramatically reduce the noiseproduced by the coil(s) when activated, (6) allow for a placebo controlgroup by making the sham and active systems less distinguishable, (7) toallow the stimulating coil to be driven continuously withoutoverheating, (8) reduce the invasiveness to a single injection at thedesired location of stimulation, and (9) make the injectable piece sosmall that it will not move around over time in an active human body.All these objectives are achieved with this embodiment, greatlyimproving the state of the art of neural stimulation.

The neural stimulator described herein may use an external coil toproduce changing magnetic fields outside the body, as in traditionalmagnetic stimulation, in conjunction with one or more tiny injectableobjects that concentrates the induced electric field to ahighly-targeted location. These systems also add a driver circuit forthe magnetic coil that allows for high voltage and fast pulses in thecoil, while requiring low-voltage power supply that could be a wearablebattery. The coil and driver circuit are also small enough to be easilywearable.

Miniaturization of the magnetic generator may be achieved using (1) anefficient driver circuit that enables thousands of volts in the coilfrom a low voltage battery, (2) a non-invasive, injectable electricfield concentrator that targets the stimulation to an area measured inmicrons, and/or (3) a fast rise time in the current of the coil thatinduces a large electric field to evoke an action potential. Each ofthese features may provide an advantage in coil power of 10 to 100×,making the total benefit over 1000×. For example, where a TMS devicewould require 10,000 instantaneous watts of electrical power in the coilto stimulate a portion of the body, these systems requires less than 10watts. This power level reduces the size of the coil, the drivercircuit, and the battery to easily wearable sizes.

Some of the systems disclosed herein use an electronic circuit to drivethe stimulator coil or coils by stimulating a pulse as a partial cycle,half cycle, full cycle, or multiple cycles of a resonance of thestimulator coil combined with a capacitor. Once the desired cycle(s) ofthe resonance are complete, the circuit remains in a quasi-steady stateor turned off until the desired time for the next pulse.

By using this approach, the inductive energy of the stimulating coil isrecycled through the capacitor, and therefore not wasted on each cycle.In addition, the voltage across the capacitor can reach hundreds orthousands of volts even when the supply voltage is very low. This highvoltage internal to the capacitor is then used to rapidly change thecurrent in the stimulating coil for the next pulse. The recycling of theinductive energy also allows for the stimulating coil to have moreturns, and therefore needs less current flow to create the same magneticfield strength. The preferred embodiment can create the needed magneticfield pulses with power supply in the range of 3 to 45 volts DC(vs. >10,000 volts for the prior art magnetic stimulation) and anaverage current flow of 0.2 to 3.0 amps (vs. 5000 amps for the priorart). In the preferred embodiment, the stimulating coil has many timesthe number of turns as the prior art coil for traditional magneticstimulation.

In some embodiments of the systems, the healthcare provider or theuser/wearer is able to (1) set the amplitude of the stimulating pulsesby adjusting the supply voltage, (2) set pulse width by selecting theappropriate capacitor, (3) set the burst frequency and number ofresonant cycles per burst by using a programmable digital pulsegenerator, (4) reverse the polarity of the stimulation by reversing theleads connecting the stimulating coil, (5) introduce asymmetry andcontrol the subsequent undershoot by adding ferromagnetic metal to thecore region of the coil or by adding a resistor in series with the coilor by changing the pulse width from the pulse generator to be less thanone resonant cycle, (6) achieve a desired penetration depth by sizingthe diameter of the coil, and/or (7) set the duration of the stimulationsession by turning the system on and off. Hence, many key parameters areeasily tuned to implement or derive the clinical or therapeutic protocolfor neural stimulation. The electronic components mentioned above may becontrolled by a microprocessor or computer to achieve pre-programmedstimulation protocols.

In one embodiment, a neuromodulation system may be provided, comprisingat least one elongate conductor configured for placement inside the bodywith one end adjacent to the site to be stimulated, and a magnetic fieldgenerator configured to be placed outside the body and to generate atime varying magnetic field perpendicular to a longitudinal axis of theconductor. The elongate conductor may comprise a material selected froma group consisting of a metal, a resistor, and carbon fiber. The metalmay be copper, tungsten, chromium, steel, stainless steel, nickel,nichrome, titanium, gold, silver, brass, or any alloy thereof. Theelongate conductor may be coated with at least one of protective layerand insulating layer. The protective layer may comprise PTFE, nylon,silicone, polyethylene, polyurethane, latex, polyimide, BoPET, or anycombination thereof. The elongate conductor may be configured forplacement adjacent to a peripheral nerve, spinal nerve, brain-stemnerve, or brain neuron or other neuron or axon. The elongate conductormay comprises a cylindrical shape with a diameter and a length, whereinthe diameter may be less than the length. The elongate conductor may bea monolithic structure with no curves or angled bends along itslongitudinal axis. The elongate conductor may comprise a wire segment orstrands of wire segments, for example. The elongate conductor may beinjected into the body through a guiding tube, such as a needle of asyringe or other implantation device. The magnetic field generator maycomprises a coil, the coil comprising one or more coil windings of wire.The magnetic field generator may be connected in parallel with acapacitor and configured such that a stimulation signal may generated,result from, or defined by a portion in time of a resonance between thecoil and the capacitor. The parallel capacitor and coil may beconfigured to be activated by a DC power supply on one side and a switchto ground on the other side, wherein a time period between the switchopening and switch closing determines the portion of the resonance thatbecomes one or more stimulation pulse or pulses. The switch may be acombination of a transistor and a rectifier and a switching action maybe configured to occur by turning the transistor on or off by applying avoltage to a gate or a base of the transistor. The switching action maybe configured to open at a beginning of a first full resonant cycle andclose prior to an end of the first cycle, at the end of the cycle, at anend of multiple cycles, or within a later cycle. The switch may beconfigured to turn off the gate or base of the transistor just prior toa series of decaying resonant pulses and then turned on to build up thecurrent in the stimulator prior to the next decaying series to saveelectrical energy consumed by current in the coil between pulse series.The parallel capacitor and coil are activated by an H driver with fourswitches. Each switch may comprise a transistor and a rectifier. In somefurther embodiments, a first two of the four switches are configured toopen and the other or second two of the four switches are configured toclose at the beginning of a first half of a resonant cycle and at theend of a second half of the resonant cycle, the first two switches areconfigured to open and the second two switches are configure to open.The magnetic field generator may comprise a stimulator coil, thestimulator coil comprising a material with high magnetic permeabilityconfigured to contain the fringe fields. The material with high magneticpermeability may comprise rigid or flexible ferrite, steel, or iron. Thecoil may further comprise a conducting ferromagnetic material thatreduces the amplitude of subsequent resonant pulses relative to theprior pulses. The material may comprise iron, cobalt, nickel, steel, oran alloy or other combination thereof. The one or more coil windings maybe in a plane or multiple adjacent planes, The one or more coil windingsmay comprise magnet wire. The one or more coil windings may comprisemetal deposited on a layered substrate. The substrate may be rigid, andmay optionally comprise FR-4 glass-reinforced epoxy laminate, glass, orhard plastic. In other embodiments, the substrate may be flexible. Theflexible substrate may comprise polyimide, BoPET, polyethylene,polyurethane, nylon, or PTFE. The system may further comprise one ormore of a microprocessor, rechargeable battery, user interface,physician interface, nurse interface, data storage, and networkconnection. The network interface may be configured to monitor orcontrol the stimulator by a computer, by the user, or by a professionalor to gather data or statistics therefrom. The elongate conductor maycomprises a monolithic body, and may lack a battery, may lack feedbackcircuitry, and/or may lack power management circuitry. The elongateconductor may comprise a discrete metal wire with a diameter of lessthan 100 microns. The elongate conductor may comprise a first end, asecond end, a body therebetween, and has a length of 10 mm or less fromthe first end to the second end, and may be configured such that neitherthe first end, the second end, or the body may be connected to anotherconductor, and/or include any curves or bends along a longitudinallength of the conductor.

In another embodiment, a method of treating a condition is provided,comprising identifying a patient with one or more implanted elongateconductors, placing a coil of an external magnetic field generatoragainst a surface of a treatment site of the patient, and applying amagnetic field to the one or more implanted elongate conductors togenerate therapeutic neural stimulation. The method may further compriseactivating the magnetic field generated to, modulate, increase ordecrease action potential activity at the treatment site. The actionpotential activity may be located in neurons in the brain, sensorysystem, or neuromuscular system. The method may be used in the treatmentof a pain disorder, mental disorder, sensory disorder, or musculardisorder, and the pain disorder may be due to amputation, neuropathy,nerve damage, or injury. The mental disorder may be depression,Huntington's disease, Alzheimer's disease, dementia, anxiety, insomnia,post-traumatic stress disorder, and/or panic attacks. The method mayfurther comprise generating the magnetic field using less than 100 peakamps and 100 volts of peak voltage.

In still another embodiment, a treatment device is provided, comprisinga syringe or injector body, a sliding plunger or pushrod located in thesyringe or injector body, a needle attached to the syringe or injectorbody, and at least one discrete elongate conductor located in thesyringe or injector body, wherein the syringe or injector body andneedle restrain the orientation of the at least one elongate conductor,and wherein the elongate conductor comprises a monolithic metal bodywith a diameter of less than 100 microns. The monolithic metal body mayhave a length of less than 10 mm.

In another embodiment, a neuromodulation system is provided, comprisingat least one elongate conductor with a length of less than tenmillimeters and a transverse dimension to the length of less than onemillimeter, configured for implantation adjacent or against a nerve,axon, or neuron, and a magnetic field generator that may be spaced apartfrom the at least one elongate conductor, and configured to generate aninduced and concentrated electric field at the at least one elongateconductor. The at least one elongate conductor may be pre-loaded in aninjection device and in a sealed sterile package. The at least oneelongate conductor may be a plurality of elongate conductors positionedserially or in parallel within the injection device. The magnetic fieldgenerator may further comprise a rechargeable battery. The magneticfield generator may be located in a housing comprising at least one ofan adjustable strap, elastic band, hook-and-loop connector, buckle,adhesive, or pin, that is configured to attach the housing a location ona human body or in attire or pockets thereof worn by the human body. Thehousing may have a height relative to a skin surface at the location onthe human body that may be less than one centimeter.

In another embodiment, a method of treating a patient is provided,comprising inserting at least one elongate conductor against or adjacentto a nerve, axon, neuron or neural tissue, wherein the conductor has alength of less than ten millimeters and a transverse dimension to thelength of less than one millimeter, positioning a magnetic fieldgenerator at a location spaced away from the at least one elongateconductor, and using the magnetic field generator to provide an inducedand concentrated electric field to at least one elongate conductor. Themagnetic field generator may be an ambulatory magnetic field generatorcomprising a housing with a plurality of magnetic coils, a drivercircuit, and a rechargeable battery. The plurality of magnetic coils hasa net thickness of less than three centimeters. The at least oneelongate conductor may be against a skin surface. The method may furthercomprise maintaining the location of the magnetic field conductor usingat least one strap, elastic band, hook-and-loop connector, buckle,adhesive, pin, or pocket.

In one embodiment, a magnetic stimulation system is provided, comprisingan external coil stimulation system configured for use against a tissuesurface of a patient, and to generate a therapeutic magnetic fieldduring therapy using at least one of 100 peak amps or less ofinstantaneous current, and a power supply voltage of 100 peak volts orless. The external coil stimulation system may be configured with anamperage limit of 100 amps or less of instantaneous current. Theexternal coil stimulation system may be configured with a voltage limitof 100 volts or less. The external coil stimulation system may beconnected in parallel with a capacitor such that a stimulation signalmay be a portion in time of a resonance between the external coilstimulation system and the capacitor. The parallel capacitor andexternal coil stimulation system are configured to be activated by a DCpower supply on one side and a switch to ground on the other side,wherein a time period between the switch opening and switch closingdetermines the portion of the resonance that becomes one or morestimulation pulse or pulses. The switch may be a combination of atransistor and a rectifier and a switching action may be configured tooccur by turning the transistor on or off by applying a voltage to agate or a base of the transistor. A switching action of the switch maybe configured to open at a beginning of a first full resonant cycle andclose prior to an end of the first cycle, at the end of the cycle, at anend of multiple cycles, or within a later cycle. The switch may beconfigured to turn off the gate or base of the transistor just prior toa series of decaying resonant pulses and then turned on to build up thecurrent in the stimulator prior to the next decaying series to saveelectrical energy consumed by current in the coil between pulse series.The parallel capacitor and coil may be activated by an H driver withfour switches. Each switch may comprise a transistor and a rectifier. Afirst two of the four switches may be configured to open and the secondtwo switches of the four switches may be configured to close at thebeginning of a first half of a resonant cycle, and wherein the first twoswitches are configured to close and the second two switches areconfigured to open at the end of a second half of the resonant cycle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is a schematic representation of a wearable stimulator coilwhich is pulse-driven by a driver circuit, using an injectable elongateconductor that concentrates the electric field induced by the coil'schanging magnetic field. FIG. 1b illustrates how the elongate injectableacts as a fraction of a turn in a secondary coil;

FIG. 2a is a schematic depiction of how an elongate conducting objectcan concentrate an electric field; FIGS. 2b-2f depict exemplary elongateconductors insulated or not insulated that are sized to be injectableand small enough, if needed, to stimulate a single nerve, nerve bundle,or neuron or group of neurons;

FIG. 3 is a graphical representation of the physical locations of theinduced and concentrated electric field of the elongate conductingobject located on a neural pathway to induce an action potential;

FIG. 4a is a schematic representation of an injectable elongateconductor positioned and oriented on a peripheral nerve; FIGS. 4b-4fshow cross-sectional views of various positions and orientations of theinjectable(s) relative to a nerve, or group of nerve fibers;

FIG. 5 schematically depicts an injectable conductor with a wearablemagnetic field generator, configured for Vagus nerve stimulation;

FIG. 6a depicts a prior-art implanted wire stimulator for deep brainstimulation; FIG. 6b an exemplary embodiment of a wirelessneuromodulation system an injectable conductor at the same location asthe prior-art electrode tips in FIG. 6a , in combination with a wearablemagnetic field generator;

FIG. 7 is a schematic circuit diagram of an embodiment of an electricaldriver circuit;

FIG. 8 is a circuit diagram of another embodiment of a driver circuit;

FIG. 9 shows the waveforms of the circuit of FIG. 8 when operating,including the (1) the pulse generator output, (2) the current in thestimulator coil, (3) the magnetic field produced by the stimulator coilwhich is proportional to the current, (4) the voltage across thestimulator coil, and (5) the electric field induced by Faraday's law ashort distance from the coil, which is proportional to the coil voltage;

FIG. 10 is an exemplary graph of the pulse shape of an action potentialevoked by the stimulator coil of FIG. 8;

FIG. 11 shows a circuit diagram of another exemplary electrical circuitthat provides for separation of the positive and negative pulses intime;

FIG. 12 depicts another embodiment of a driver circuit of the idealcircuit depicted in FIG. 11;

FIG. 13 shows the waveforms of the circuit of FIG. 11 when operating,including the following: (1) the pulse generator output, (2) the currentin the stimulator coil, (3) the magnetic field produced by thestimulator coil which is proportional to the current, (4) the voltageacross the stimulator coil, and (5) the electric field induced byFaraday's law a short distance from the coil, which is proportional tothe coil voltage;

FIG. 14 shows an oscilloscope trace of the coil voltage of the drivercircuit of FIG. 8 built and combined with an exemplary stimulator coil;

FIG. 15 shows an oscilloscope trace of the coil voltage of the drivercircuit of FIG. 8, with the addition of a metallic and ferromagneticcore into the coil;

FIG. 16 is an exemplary embodiment of a stimulator coil with windingslocated in the periphery of the plastic spool, with a single-turninduction coil to pick up the induced voltage from the coil whenactivated;

FIG. 17 are the oscilloscope traces of the voltages in the stimulationcoil and the induction coil when activated by the circuit of FIG. 8 whenthe pulse width of the pulse generator is widened to allow for oneresonant cycle;

FIG. 18a and FIG. 18b show the induced voltage when the pulse width ofthe pulse generator in FIG. 8 is widened to allow for two or moreresonant cycles;

FIG. 19 shows the induced voltage when the pulse width of the pulsegenerator is shortened to allow for only a partial resonant cycle ofcircuit of FIG. 8, creating a symmetric stimulation signal;

FIG. 20 shows the induced voltage when the pulse width of the pulsegenerator is shortened further to allow for only the positive portion ofa resonant cycle of circuit of FIG. 8, for stimulation protocols thatrequired only one polarity of charge;

FIGS. 21a and 21b show the placement of high-permeability material onthe first and second opposing faces, respectively, of a planar, spiralstimulator coil;

FIGS. 22a and 22b are perspective view of an exemplary flattened ovalstimulator coil with and without high permeability materials,respectively;

FIGS. 23a to 23f illustrate how the injectable conductor is placed neara nerve of the a part of the body with an injection from a syringe;

FIG. 24 shows the microscope and electrophysiological system of anexperiment to stimulate action potentials in a live brain slice takenfrom a mouse under a microscope.

FIG. 25 is a microscope image of an injectable conductor placed in abrain slice;

FIG. 26 is a microscope image of the tip of the injectable conductor anda sensor placed on a nearby neuron to detect action potentials;

FIG. 27 shows the resonant pulse of the voltage in the stimulator coilduring the experiment and the pulse generator displaying thestimulator's pulse rate;

FIG. 28 shows the oscilloscope tracing of the resting potential of asensed neuron when the stimulator is turned off;

FIG. 29 shows the oscilloscope tracing of action potentials of thesensed neuron when the stimulator is turned on;

FIG. 30 depicts an exemplary system hardware architecture for thewearable system; and

FIGS. 31a and 31b depict an exemplary software architecture for thewearable system, comprising a power saving mode and a pulse shapeflexibility mode, respectively.

DETAILED DESCRIPTION

One exemplary embodiment of this neural stimulation system comprises anexternal or wearable portion containing a magnetic field generator thatmay be coupled to the external surface of the patient, and an internalor implanted injectable portion that concentrates the electric field ofthe stimulator to activate only a targeted a nerve fiber or neuron orgroup of nerve fibers or neurons. As depicted in FIG. 1a , theneuromodulation system 7 comprises a wearable portion 3 comprises astimulator coil 1 that is driven by a driver circuit 4 and powered by abattery 5 and/or other power source. The driver circuit 4 may contain aprocessing or computer unit to generate the drive signals to thestimulator coil 1 and to receive input to allow for adjustments instimulation parameters from the user or healthcare provider, via aninterface to a smartphone or other device, over a WiFi, Bluetooth, RFID,or similar network or wireless protocol, at the location of the user orfrom a remote location. The wearable portion 7 is attached to the bodyby straps, elastic bands, Velcro, buckles, adhesives, pins, or similarmechanism, with the stimulator coil(s) facing the skin. Alternatively,the wearable portion may be attached to clothing or other attire usingpockets, clamps, pins, adhesives, Velcro, or other suitable attachmentmeans. Within the clothing or attire, the appropriate location of thewearable portion depends on the location and type of stimulation.

The current flowing in the stimulator coil 1 of FIG. 1a produces achanging magnetic field that easily penetrates deeply into the body,including the hard and soft tissue. This changing magnetic field, byFaraday's law of electromagnetics, induces an electric field that isconcentrated in one or more injectable portion or components 3 that alsopenetrates the body. In the some embodiments, this induced electricfield is may be configured to generate with a larger area effect, or asmaller localized effect to alter the body's neurological system exceptat the immediate location of the injectable conductor 3. The changingmagnetic field from stimulator coil 1 induces an electric field whichmoves the free electrons in the injectable conductor 3, causing oneend-point to be positively charged while the other end is negativelycharged. This induced voltage between the endpoints of the injectableconductor 3 then acts like two electrodes placed at the endpointlocations and activated with a voltage. This activation moves ions nearthe tip of injectable conductor 3 and evokes an action potential orstream of action potentials at nearby neuron(s) or axon(s) if the tipvoltage is sufficient to raise the resting potential to beyond thetrigger potential.

A wide variety of coils may be used with various embodiments of theneural stimulator. The number of turns can vary from 20 to 300, or about40 to about 200, or about 10 to about 150, or more. More turns increasethe inductance of the coil, which increases the voltage rating of thetransistors and rectifiers in the driver circuit, but lowers the currentrequired to produce a given magnetic field.

The diameter of the coil turns is may be selected based on thepenetration depth needed for stimulation. In some embodiments, thediameter of the coil is approximately four times the penetration depthrequired. Some nerves are within 1 cm of the skin surface, making a 4 cmdiameter coil about the right size. Other stimulation locations such aswithin the spinal cord of an obese person could be 10 cm deep, makingthe optimal coil diameter around 40 cm for the lowest power consumption.In this case, a smaller coil driven with more power might be morepractical. Unique coils such as H coils and figure eight coils have beenshown to generate a stronger or more concentrated magnetic at a certainpenetration depth, and these coils could be advantageous to use withthis stimulator. In some variations, the coil diameter (or averagetransverse dimension) is then in the range of about 2 cm to about 50 cm,or about 3 cm to about 40 cm, or about 4 cm to about 25 cm.

The diameter of the wire used within the coil determines the electricalresistance of the coil and hence how much heat it generates given theamount of current required to generated the needed magnetic field at theinjectable location. Smaller diameter wires generate more heat thanlarger diameter wires, but larger diameter wires add more weight to thewearable portion of the stimulator. In most embodiments, the diameter ofthe wire is between 0.3 to 2.3 mm in diameter, with the smaller diametertypical for lower penetration depths. In other embodiments, the wirediameter or width may be in the range of about 0.5 mm to about 3 mm, orabout 0.4 mm to about 2.5 mm, or about 0.2 mm to about 3 mm.

The coil for the neural stimulator may be configured to generate amagnetic field strength between 0.001 and 0.1 Tesla to induce asufficient voltage at the injectable to stimulate action potentials. Themagnetic field strength may be smaller for narrower pulse widths becausethe induced voltage is proportional to the time derivative of themagnetic field. In contrast, prior-art TMS systems require magneticfield strengths of 1-5 Tesla because the induced electric fields notconcentrated by an injectable as described herein. The magnetic fieldstrength described herein can be achieved with coil currents of 2 to 20amperes instantaneous during pulse bursts and 0.2 to 5.0 amperes averagein embodiments that turn off between bursts. In contrast, prior art TMSsystems require hundreds or thousands of amperes instantaneous coilcurrent.

The pulse width, burst rate, leading pulse amplitude, and leading pulsepolarity (polarizing or depolarizing of the axon or neuron) are definedby the stimulation protocol and are typically the same for this NeuralStimulator as required for prior-art wired electrode systems, subject tothe resonant characteristics of this stimulator. Typically, the pulsewidths are 20 microseconds to 1 millisecond, the burst rates are 10 Hzto 200 Hz. The leading pulse amplitude of prior-art wired electrodestypically generates 10 microamperes to 1500 microamperes of polarizingor depolarizing current, but the actual current needed at the axon orneuron is 10-20 microamperes. Larger currents are needed because ofdispersion, that may results from the electrodes not being positionedclose enough to the axon or neuron, or if there is a significantmyelination or perineural layer between the implant component and theaxon or neuron. In this Neural Stimulator, the injectable is placed asclose as possible to the nerve, nerve bundle, nerve fiber, or neuron tobe stimulated. Hence, the current produced by the injectable is 10 to 50microamperes, which in turn requires 20 to 100 millivolts between theendpoints of the injectable for myelinated peripheral nerves or 10 to 20millivolts for unmyelinated axons or neurons. Depending of the length ofthe injectable, the electric field strength needed at the injectable isbetween 1.0 volts/meter for 10 millivolts coupled with a 10 mminjectable, and 100 volts/meter for 100 millivolts coupled with a 1 mminjectable.

The leading stimulation pulse may be repeated within bursts of pulses.Often, it is desired for each burst to contain both positive andnegative pulses to avoid charge buildup in the nervous system. Multiplebursts of stimulation generally cause the body to generate multipleaction potentials.

Action potentials of the human body are typically pulse-frequencymodulated, meaning that the intensity of the signal is determined by therepetition rate. Hence, the driver circuit 4 in FIG. 1 will repeat thestimulation burst at the desired repetition rate. In many therapies andapplications, it is not necessary for the stimulated voltage waveformsto mimic the body's action potential waveform, because the body producesits own action potentials in response to a variety of stimulation pulseshapes from the stimulator. However, pulses that are too short in timemay not stimulate the nerve and pulses that are too long in time may notachieve the burst rate required for the desired effect.

Referring back to the exemplary neuromodulation system in FIG. 1a theneural stimulator may be characterized as a transformer, wherein theinjectable conductor 3 is a like a secondary winding having a fractionof a turn. For example, the induced voltage in the injectable conductor3 may be characterized as a fraction I/L of the induced voltage in asingle-turn induction coil 2, of FIG. 1b where I is the length of theinjectable 3 and L is the length of the single-turn induction coil 2.This relationship is one way to determine the induced voltage at theinjectable conductor 3, which is otherwise difficult to measure.

Another consideration of the function of injectable conductor 3 of FIG.1a is as an electric field concentrator. Any elongate conducting objectwill naturally concentrate the electric field surrounding it asillustrated in FIG. 2a . FIGS. 2b-2f shows an elongate straightconductor in the shape of a cylinder which comprises the injectableconductor 3, and this conductor could have an insulating layer, or not,with conducting portions exposed on each end. Note that the injectableconductor 3 in FIG. 2b of the could be a segment of the long wires usedin implanted stimulators. These wires are already available on themarket and have already been tested to be safe inside the human body forextended periods. In the depicted embodiment, the cross-sectional shapeof the conductor along its length is uniform, but in other examples, thecross-sectional shape or size may vary along its length. In otherexamples, the conductor may have an arcuate shape or one or more angularbends.

The amplitude of the induced voltage V₂(t) produced by the stimulatorcoil 1 in FIGS. 1a and 1b is proportional to the length I of theconductor by the formula V₂(t)=(I/L)*A*dB/dt, where L is the length ofthe single-turn induction coil. A is the cross-sectional area of thesingle turn induction coil. The area A of single turn induction coil 2in FIG. 1b is (L/4)². B is the magnetic field produced by the stimulatorcoil, which is, in turn, proportional to the electrical current flowingin the stimulator coil.

The cross-sectional dimension of the stimulator coil L/4 is typicallybetween 1 and 20 cm, which needs to be small enough to be comfortable asa wearable, but also have a penetration depth to reach the injectableconductor. Some stimulation sites for the injectable like the Vagusnerve are within 1-2 cm, but other stimulation sites like the spinalcord could be 20 cm deep for an obese patient.

The length of the injectable conductor from a first end to a second endis typically between 1 and 10 mm. The conductor is separate, the firstend, the second end, or the body of the conductor not attached to anyother conductor structure, but may be optionally coated with a materialas described herein to modulate the biocompatibility of the conductorwithin the body of a patient. In some variations, the conductor isstraight, with no curves, angled bends or branched segments. In othervariations, the conductor may have a curve or angled bend region, butwherein the curb or angle is angled no more than a total of 5 degrees,10 degrees, 15 degrees, 20 degrees, 25 degrees, 30 degrees, 35 degrees,40 degrees or 45 degrees. In some examples, lengths in this range may belong enough to produce sufficient induced voltage to stimulate but shortenough to not cause complications in the body such as displacement frombodily movement, feeling of discomfort, and interference withsurrounding tissue. In some cases, the injectable could be as long as100 mm if it is located in the chest or spine. A longer injectablegenerates a higher induced voltage at the endpoints, which may providelower power and longer battery life for the wearable field generator. Inother examples, the conductor may have a length of about 2 to 30 mm, 4to 20 mm, or about 3 to 15 mm. The diameter or transversecross-sectional dimension relative to the longitudinal axis of theinjectable conductor is typically between 8 and 50 microns, which isthick enough to apply a voltage over a sufficient area of the nerve orneuron and be physically strong enough to not bend during normalactivity of the body, but also be thin enough to be injectable through asyringe or other injection device. These thin injectables are effectivefor highly targeted stimulations for single nerve fibers or small groupsof fibers or neurons. For large nerve bundles and for musclestimulation, the cross section of stimulation should be large, and inthese cases the injectable could have a diameter of up to 4 mm and stillbe accommodated by standard gauge syringe needles.

As noted previously, certain embodiments of the neural stimulator onlyutilize an injectable device, i.e. a small and very thin cylindricaldevice that can be placed by a syringe, making this system essentiallyminimally invasive. Prior art stimulators that require a coin, pill, orlong antenna type implants require significant surgery to be placedinside the body, and these must be connected to a power source that isalso located inside the body, which may require tissue dissection toimplant the component(s). In other examples, a portion of a magneticinduction charger system is located inside the body and other partoutside, requiring two coils with close spacing between them, like thestimulators available from Bioness (Valencia, Calif.). The RF-coupleddevices from Stimwave (Pompano Beach, Fla.) uses RF coupling and requirea long 45 cm antenna inside the body to reach the spinal cord area.Another RF-coupled wireless stimulator from Advanced Bionics (Valencia,Calif.) and described in U.S. Pat. No. 6,735,474 B1 has a smallerhelical antenna, but the internal battery can only be rechargedwirelessly when it is located very near the surface of the skin. RFcoupling incurs losses when attempting to travel even small distancesinto the body. In contrast, certain embodiments of the neural stimulatordescribed herein use magnetic coupling, reducing the size of theimplanted portion considerably to be merely injectable. Due to theirlarger, heavier, and more complex configuration, existing implants tendto have more complications and potential problems. Their weight causesgreat shifts during bodily movements, and the long antennas or wires canbe pulled out of place by natural bodily motion. In contrast, the smallinjectable devices of the embodiments of the neural stimulator are notheavy enough to be displaced with bodily motion, and not long enough tobe susceptible to pulling out of place.

FIG. 2c shows an elongate straight conductor wherein the insulation isstripped off the same amount on each end. The surface area of theexposed conducting material determines the current density on theendpoints of the elongate conductor when activated by the fieldgenerator. By controlling the length of the stripped portion of theinsulation, the current density exposed to the tissue can be controlledto avoid damaging the tissue while still achieving stimulation. FIG. 2dshows an elongate conductor wherein the insulation stripped off isdifferent on one endpoint than the other endpoint. This difference cancause one end to have sufficient current density to trigger an actionpotential in the targeted nerve or neuron and the other end to haveinsufficient current density for stimulation for untargeted nerves orneurons. In large nerves or in the brain, there will likely be caseswhere the other endpoint of the injectable should not trigger actionpotentials to prevent side effects. Without limitation, the currentdensity of one endpoint vs. another could also be achieved withdifferent conductor diameter at each end in FIG. 2b , or by having athicker or less conductive coating on one end vs. the other. Theinjectable could also be pre-formed into a curved or semi-circularshape, as illustrated in FIG. 2f . In this case, the injectable could betemporarily straightened while inside the syringe and then re-take thisshape as it leaves the syringe, if at least one material comprising theinjectable is elastic. FIG. 2e shows two injectables that generate aninduced voltage between the two inner endpoints that is twice thevoltage generated by one injectable. This configuration in FIG. 2econcentrates the current flow in the nerve or neuron very preciselybetween the two inner endpoints, allowing for better targeting andstronger stimulation.

The injectable conductor 3 could, without limitation, be copper,tungsten, chromium, stainless steel, nickel, nichrome, titanium, gold,silver, brass, any alloy of these, or any other conducting material. Or,the conductor may contain carbon, carbon fiber, or other resistivematerial in all or part, to limit the current flow to a safe level forhuman tissues. However, in some embodiments, the non-ferromagneticmaterials may be used to reduce the potential interference with MRIdiagnostics and because of magnetic attraction forces between theinjectable and the magnetic field generator. Again, without limitation,the conductor could be partially or completely coated or insulated withPTFE (polytetrafluoroethylene), PET (polyethylene terephthalate), nylon,silicone, polyethylene, polyurethane, latex, polyimide, BoPET(biaxially-oriented polyethylene terephthalate), any mixture orcombination of these, or other suitable insulator to protect theconductor from corrosion and/or to prevent the surrounding tissue fromreacting adversely. The thickness of the insulation is typically 5 to100 microns, thick enough to resist or avoid pinholes, scratches, ortears, but also thin enough to allow passage through a syringe or otherinjection device. The exposed conducting portion of the injectableconductor may be coated or plated with yet another conducting materialis that more compatible with bodily tissue.

The injectable conductor 3 in FIG. 3 creates a voltage between each end,so placing one end near a nerve or neuron can stimulate actionpotentials. The pulse width, number of resonant cycles per burst, andburst frequency of this induced voltage is completely controllable fromthe wearable portion 7 of FIG. 1. This wearable portion can emulate thenatural stream of action potentials, create bi-phasic and charge-neutralpulse shapes that have been shown to be benign, or achieve any otherdesired pulse shapes for the recommended stimulation protocol.

Furthermore, the injectable conductor 3 of FIG. 3 can be small enough indiameter or transverse cross-sectional shape to target a single nervefiber or neuron, or be larger to stimulate a larger area possiblyincluding more than one neuron or multiple nerve fibers or an entirenerve. Without limitation, the injectable conductor 3 could havemultiple strands at one or both ends to stimulate multiple locationssimultaneously, or multiple injectable conductors could be injected.Without limitation, some or all of these strands could flare out afterplacement inside the body to help keep the conductor positioned over along period of time and during bodily motions. Some treatments requiremultiple nerves, nerve fibers, or neurons to be stimulatedsimultaneously. For example, one muscle may require many nerve fibers tobe stimulated to achieve full muscle movement. In the brain, often manylocations need stimulation to treat a general disorder like anxiety ordementia. In these cases, multiple strands of conductors on a singleinjectable or multiple injectable conductors could be placed, and onestimulator coil could stimulate all of them or multiple stimulator coilscould be used.

Stimulator-Body Configurations

FIG. 4a shows how this neural stimulator may be used to excite aperipheral nerve in the human arm. injectable conductor 3 is placed withone end on the nerve to be stimulated. This end should be located on ornear the nerve fiber or on or just inside the cell membrane of the axonto be stimulated. The active endpoint of the injectable may be situatedjust outside the myelin layer of the nerve fiber or penetrate the myelinlayer or be located just outside the nerve fiber bundle or penetrate theperineurium layer. The stimulation voltage amplitude at the injectableneeds to be around 100 millivolts to stimulate the nerve through themyelin or perineurium layer. If the endpoint of the injectable istouching the nerve fiber or neuron itself, then only about 15 millivoltsof amplitude is required at the injectable. See the 15 millivoltsdifference between the resting potential and the trigger potential ofthe action potential in FIG. 10, which defines the minimum voltageneeded to stimulate.

The other endpoint of the injectable in FIG. 4a and the rest of theinjectable conductor should be oriented to avoid nerves and neurons thatshould not be stimulated, and avoid tissue that could be adverselyaffected. The orientation should also be such that normal body movementsdo not cause the active endpoint of the injectable conductor to shift inposition over time. For minimal power consumption and maximumstimulation intensity, the long dimension of the injectable should bealigned with the induced electric field from the coil. Based onFaraday's law of induction, the long dimension of the injectableconductor should be parallel to and as close as possible to the windingsof the stimulator coil, and away from the center point of the coil.

In general, the closer that the endpoint of the injectable is placedrelative to the nerve, nerve fiber, or group of nerve fibers or neuronsto be stimulated, the lower the power consumed by the wearable, whichcan prolong battery life or reduce battery size. In many neuralstimulation protocols, an entire nerve or group of nerve fibers must bestimulated in order to achieve the desired result. In a human being, thediameter of some nerves can be up to 5 millimeters. And, somestimulation protocols call for certain nerve fiber bundles in a nerve tobe stimulated preferentially relative to other fiber bundles wherein allfiber bundles are located within the same nerve. FIG. 4b show the crosssection 40 of an exemplary nerve containing three fiber bundles 41. Thenerve itself, each of the fiber bundles, and each of the fibers arewrapped in a sheath that is highly insulating. For this reason, in somemethods of using neural stimulator, may involve placement of theinjectable conductor inside the nerve, as illustrated in FIG. 4b andhave this injectable stimulate the fiber bundle that is closest. Or, twoinjectables illustrated in FIG. 4c may be placed opposite the nervecross section and generate an induced voltage on either side of thenerve, and this induced voltage is twice that of the single injectableof FIG. 4b . FIG. 4d shows how multiple conductors could be placed,either with multiple injections or by having multiple strands in oneinjectable. FIG. 4d also shows how the injectables can be placed offcenter to preferentially stimulate the fiber bundles in the lowerportion of the nerve cross section. In some stimulation sites, thelocation of the target fiber bundle inside the nerve is not known. Inthis case, it is desirable to have a set of injectables that can addressdifferent bundle locations. FIG. 4e shows such a configuration. Twoinjectables are placed above and below the nerve, and another two areplaced on each side. Here, the rotational orientation of the wearablefield generator will determine which of the four injectable endpointscreates the strongest polarization of the axons, allowing for one ofseveral different fiber groups to be preferentially stimulated relativeto the other three. FIG. 4f shows the curved injectable, which can hugthe nerve and stay in place more effectively, similar to the cuffelectrodes that are implanted today. The exposed conductors on eachendpoint of the injectable in FIG. 4f create a stimulation across thenerve's diameter. Without limitation, the endpoints of the curvedconductor could be off center relative to the nerve to preferentiallystimulate a fiber bundle that is also off center in the same direction.

The wearable stimulator 7 is placed on the skin near the injectableconductor 3 in FIG. 4. Without limitation, the wearable portion 7 couldbe driven by a circuit or microprocessor that senses an upstream neuralactivity and uses the Neural Stimulator to bridge to the peripheralnerve externally. In this example, these systems could be used as partof another system to bypass nerve pathways damaged by neuropathy,injury, amputation, or another ailment.

FIG. 5 shows how this neural stimulator can be used to excite the Vagusnerve. In this case, the injectable conductor 3 is placed with one endon the Vagus nerve or pathway to be stimulated, and the wearable portion7 is placed close by but outside the body. Without limitation, theNeural Stimulator can help treat epilepsy or other ailment that isalleviated by Vagus nerve stimulation. Known stimulation sites andindications, respectively, are hypoglossal nerve for Obstructive SleepApnea, posterior tibial nerve for bladder control, the sensingperipheral or spinal nerve for pain relief, Occipital nerve formigraine, and Vagus nerve for epilepsy.

FIG. 6b shows how an embodiment of the neural stimulator can be used toexcite neurons in the deep brain region. In this case, the injectableconductor 3 is placed with one end at the location in the brain wherestimulation is desired. The wearable portion 7 is placed close by butoutside the head. Without limitation, the neural stimulator can treatAlzheimer's, dementia, anxiety, insomnia, post-traumatic stressdisorder, panic attacks, and seizures by placing the injectableconductor in the deep brain such as the hypothalamus, fornix, entorhinalcortex, nucleus basalis or other areas of the brain.

Without limitation, the injectable conductor 3 shown in FIGS. 4, 5, and6 b may be placed with a syringe or other injection system and be guidedto the proper location by instantaneous imaging. This imaging could bemagnetic resonance imaging (MRI), X-Ray imaging, ultrasound, or otherbody imaging system.

In these examples and many others, the neural stimulator may greatlyreduce the invasiveness of the prior art stimulators, an example ofwhich is illustrated in FIG. 6a . Prior art targeted stimulators requireextensive surgery, long wires, large implants, and implanted batterycharging or and periodic removal and replacement of the battery. Theserepresent great technical challenges for both doctor and patient, andincur very high costs of implementation.

Driver Circuit for Stimulator Coil

The driver circuit of this neural stimulator manages the appliedvoltage, current, and power consumption of the stimulating coileffectively to reduce one, two, or all three of these quantities.Relative to the existing magnetic stimulators, various embodiments ofthe neural stimulator coils described herein may have more turns, whichcan generate the same magnetic field strength with less current flow.The higher number of turns means that this neural stimulator coil has ahigher inductance, or stores more energy. This energy may be stored inthe coil as a DC current in between pulses and is reciprocated to andfrom a parallel capacitor when generating a pulse. Alternatively, the DCcurrent may be gradually erased between pulses, saving even more energy.

The driver circuit's pulse changes current rapidly in the coil creatinga rapidly changing magnetic field, thereby creating the large electricfield, by Faraday's law, a few centimeters away and inside the body. Thevoltage generated in the capacitor can be many times greater than thesupply voltage required of the circuit. Hence, the driver circuit canuse high voltages to achieve a rapid change in current in thestimulating coil, but does not require a high voltage supply.Furthermore, the injectable conductor 3 of the neural stimulator reducesthe total magnetic energy required to stimulate action potentials,further reducing the power needed in the external coil. All thesemechanisms together render the neural stimulator a far superiorapparatus for stimulating electricity in the body than the prior artmagnetic stimulators.

One embodiment of an exemplary driver circuit is depicted in FIG. 7,where the stimulator coil 1 is connected in parallel with a capacitor72, and this sub-circuit is called a resonant circuit. One side of theresonant circuit is connected to a low voltage power supply 73. Theother side is connected through an analog switch 74 to ground 75. Thepower supply allows current to flow in the stimulator coil when theswitch is closed and completes the circuit. The parallel capacitorstores and recycles the high-voltage electrical energy required for thenext pulse in the stimulation burst. The switch can additionally turnoff power in between bursts to minimize power consumption further.

FIG. 8, depicts another embodiment of the drive circuit. Compared toFIG. 7, the switch 74 of FIG. 7 is replaced by a series connection of arectifier 82 and an N channel MOSFET 83. The pulse generator 81 drivesthe gate of the MOSFET 83 to turn it on and off. A MOSFET 83 normallyfunctions as an ideal switch, but only when the drain-source voltage ispositive. Because the drain-source voltage can sometimes be negative, aswill be described later, the rectifier 82 is added in series to preventthe MOSFET 83 from seeing a negative drain-source voltage and preservingcharacteristics of an ideal analog switch that is open. The pulsegenerator 81 generates a voltage that turns on and off the MOSFET 83gate.

FIG. 9 shows the waveforms that are generated by the circuit of FIG. 8when activated by the pulse generator. Most of the time, pulse generatoroutput 91 keeps the gate of MOSFET 83 of FIG. 9 turned “on”, but turnsit off when a stimulating pulse needs to be created. When the MOSFET 83of FIG. 8 is turned on for a while, the coil current 92 in FIG. 9 willreach steady state defined by the voltage across the coil divided by itselectrical resistance. This steady coil current 92 remains until thepulse generator output 91 drops and thereby the MOSFET 83 gate of FIG. 8turns off. At this time, the resonant behavior of the stimulating coil 1and the capacitor 72 of FIG. 8 will begin. In this preferred embodiment,the resonance is aborted after one cycle as the pulse generator output91 turns the MOSFET 83 gate of FIG. 8 back on. At this time, the steadycoil current 92 is restored and the resonance stops.

During the resonant cycle, the coil current 92 follows the shape of oneperiod of a cosine wave. As expected from general circuit theory for aninductor, the coil voltage 93 will follow the derivative of the coilcurrent 92, and hence appears as one period of a sine wave. The periodof this sine wave, which is also the width of the biphasic stimulationpulses is equal to SQRT(LC) where L is the inductance of the stimulatorcoil and C is the capacitance of the parallel capacitor. The inductanceof the stimulator coil typically ranges from 0.1 to 20 millihenries, andthe capacitance of the parallel capacitor ranges from 0.1 to 10microfarads. The coil voltage 93 must stay below the rated voltage ofavailable MOSFETs or IGBTs and rectifiers, which is typically 1000-2000voltage. The system may be configured so that the current pulse 92amplitude does not exceed the instantaneous current available from atypical wearable battery and supply capacitor, which is typically about20 amps, but in other embodiments may be in the range of 1 to 10 amps,10 to 30 amps, or 30 to 100 amps, for example. The RMS average currenttimes the RMS average voltage in FIG. 9 must not exceed the power ratingof a wearable power supply, which is 10 to 12 watts for a standard USBbattery used to charge smart phones, for example. The power is alsolimited by the time needed between charging of the wearable battery,which is 50 watt-hours (10 watts for 5 hours) for a one-pound batteryusing Lithium Polymer chemistry.

Typically, the pulse widths are between 50 microseconds and 1millisecond, but in other examples could be in the range of 10 to 50microseconds or 1 to 100 milliseconds, with multiple, preferablybiphasic, bursts. Typically, the burst frequencies vary from 10 Hz to100 Hz, but in other examples could be 1 Hz to 10 Hz or 100 Hz to 1000Hz. In some embodiments, relatively narrower pulses with higher burstfrequencies may be used, while in other embodiments, relatively widerpulses with lower burst frequencies, if the aforementioned ranges aremaintained. The ranges of current, pulse width, and burst frequency arealso dependent on the degree of stimulation needed. For example, somestimulation protocols just need to regenerate background levels ofneural activity while others need to evoke the maximum rate of actionpotentials of the body. Stimulating muscle movements, for example,require strong stimulations to recruit most or all the muscle fibers toact together as each one is activated by a single nerve fiber. Theranges of current, pulse width, and burst frequency could also bedependent on how close the injectable is placed to the target nerve ornerve fibers or neurons to be stimulated. In some cases, the targetnerve group or nerve fiber may be deep within the nerve, and thestimulation from the injectable must traverse one of more fascicles,which shield the stimulation energy, possibly differently for somefrequencies versus others. For example, if higher frequencies ofstimulation from the injectable are attenuated by the soft tissues inthe body, then the wider pulse widths and lower burst frequencies wouldtraverse these tissues with less attenuation than narrower pulse widthsand higher burst frequencies. The location of nerve groups within anerve and nerve fibers within a group are not always the same from onepatient to another, and the injectable may need to stay a safe distanceaway to prevent nerve damage throughout the life the patient. The neuralstimulator embodiments described herein can achieve a range ofstimulations using the injectable conductor combined with the wearablestimulator. In FIG. 9, the burst rate of stimulation is set by thefrequency of the pulse generator output 91. The elapsed time between thestart of stimulation pulses to the termination of pulses, or burstwidth, is set by the pulse width of the pulse generator output 91 (FIG.9 shows a width of one resonant cycle, but a longer pulse output wouldcreate multiple resonant cycles). Finally, the stimulation pulse widthis determined by the resonant frequency of the stimulator coil and theparallel capacitor, and this resonant frequency can easily be adjustedby changing the capacitance of the parallel capacitor. Hence, all keyparameters of known and desirable wired stimulations systems can beaccommodated by the driver circuit design of FIG. 8.

The magnetic field created by a coil is proportional to the currentflowing within the coil. Hence, the coil current 92 waveform in FIG. 9also represents magnetic field 92 emanating from the coil andpenetrating the body.

Similarly, Faraday's law states that the induced electric field in spaceof an electromagnetic wave is proportional to the derivative of themagnetic field. For this reason, the coil voltage 93 waveform in FIG. 9also represents the electric field 93 emanating from the coil andpenetrating the body. It is this electric field that evokes ordepolarizes the action potentials normally appearing the body or thebrain, at the location of the injectable conductor.

The electric field created by the neural stimulator embodimentsdescribed herein and shown in the Electric Field 93 of FIG. 9 can beoriented to further evoke the natural action potentials already existingin the body, or could depolarize them by reversing the leads on thesimulating coil 1 of FIG. 8.

One way to reduce the amplitude of the undershoot in coil voltage 93 ofFIG. 9 is to add some ferromagnetic metal around the coil opposite theside facing the body. The presence of the metal will create eddycurrents, which will turn into heat. These losses will make theresonance die out faster, and hence make the undershoot have smalleramplitude than the initial pulse. Another way to reduce the amplitude isto add a resistor in series or in parallel with the stimulator coil 1.The resistor heat has the same effect as the eddy currents, hencereducing the amplitude of the undershoot relative to the main pulse.

FIG. 11 shows yet another embodiment of a neural stimulator system. Theresonant combination of the stimulating coil 1 and parallel capacitor 72is now driven bi-directionally by an H-driver. The H driver has fouranalog Switches 74, and the resonant circuit is situated in the centerof the H. Power is supplied through one of two switches to the two upperlegs of the H, and ground is connected through one of two switches tothe two lower legs. Two switches, upper left and lower right are turnedon to flow current into this resonant circuit on one direction, and theother two switches, upper right and lower left are turned on to flowcurrent in the opposite direction. This circuit can separate, in time,the electric field 93 cosine wave pulse of FIG. 9 into two pulses, onepositive and one negative. The waveforms for this approach will bedescribed later below.

FIG. 12 shows the circuit of FIG. 11, but with each of the upper analogswitches described for FIG. 11 replaced by a series connection ofp-channel MOSFETs 121 and rectifiers 127 and the lower analog switchesreplaced with a series connection of n-channel MOSFETs 83 and rectifiers127. This H-driver circuit with these components is in a standardH-driver configuration used for other reversible drive systems like DCmotors. As in FIG. 8, the rectifier 127 is added to allow the MOSFETs 83and 121 to behave like an ideal analog switch regardless of the polarityof voltage. Also, the MOSFET 121 is a P channel MOSFET to facilitateswitching current from the power supply instead of to the ground, forwhich the N channel MOSFET is designed. The pulse generator output 131drives the gates of one pair of MOSFETs 83 and 121, and the inverse ofthe pulse generator output 131 drives the gates of the other pair. Inthis case, the MOSFETS 83 and 121 pairs are always driving current inone direction or the other.

FIG. 13 shows the waveforms of the coil current 132 and coil voltage 133for the circuit of FIG. 12 when activated by the pulse generator output131. This embodiment allows for the stimulating coil 1 to have, whileall switches are open and resonance is allowed to occur between thestimulator coil and the parallel capacitor, the half-cosine positive andhalf-cosine negative pulses separated in time. A positive electric field133 half-cosine pulse is created in the body when the stimulating coil71 experiences a positive current transition, and a half-cosine negativepulse is created on a negative current transition. In biphasicstimulation, the desire is to avoid buildup of charge in the body. Thiscan be accomplished by having pulses of the opposite polarity occurafter the leading pulse. The circuit of FIG. 12 and its waveforms inFIG. 13 allow for the charge from the leading pulse to be removed laterin time. The time between these pulses of opposite polarity allows foran additional degree of freedom in the stimulation protocol. Forexample, this separation of the positive from negative pulses mightallow for the amplitude of the pulses to be less since the negativepulse can be delayed until the refractory period of the actionpotential. During the refractory period, the negative pulse does notnegate some of the effects of the leading pulse, but still preventscharge build-up.

Without limitation, the rectifier in FIGS. 8 and 12 may each be multiplerectifiers ganged together in series or in parallel or both todistribute the current and voltage and stay below the rated voltageand/or rated current of each individual rectifier. Also withoutlimitation, the MOSFETs of FIGS. 8 and 12 may each have multiple MOSFETsconnected in parallel or series for the same purpose. In addition, theseMOSFETs could be replaced by Insulated Gate Bipolar Transistors (IGBTs),Darlington transistors, or bipolar transistors, without limitation. Alsowithout limitation, the output of the pulse generator may originate froma microprocessor-based controller or computer and have multipletransistor driver stages to adequately turn on and off the MOSFETs orother driver transistors. Again, without limitation, multiple instancesof this driver circuit could be used to drive multiple coilssynchronously for the electric fields of the multiple coils to addtogether in a focused region, or subtract to remove stimulation where itis not wanted, or any combination of these. The double coil used byBrainsway (Jerusalem, Israel) is an example of where two coils are usedto better focus the magnetic field inside the brain and improve theresolution of treatment for magnetic stimulation.

Driver Circuit Design

The circuit illustrated in FIG. 8 was built wherein the stimulator coil1 was an air-core coil of approximately 500 turns of 18 AWG (AmericanWire Gauge) copper magnet wire, wrapped on a spool of 2.0 centimeterinner diameter, 5.0 centimeters outer diameter, and 4 centimetersthickness. The capacitor 72 was 0.5 microfarads rated at 2000 volts, andis available from Digikey as part number 338-4169-ND. The rectifier 82was rated at 1000 volts and 3 amps, and was available from Digikey aspart number 1N5408-E3/54GICT-ND. The N channel MOSFET was implemented asfour MOSFETs ganged together in parallel and each one was rated at 1200volts. The MOSFETs are available from Digikey as part number1242-1164-ND. The power supply 73 was variable up to 30 volts DC and 10amps. The pulse generator 81 is available from BK Precision as partnumber 4030.

FIG. 14 shows the oscilloscope waveforms of this preferred embodiment ofFIG. 8 using the parts described. The pulse generator output 91 (uppertrace) is at 8 volts most of the time, which turns on the MOSFET and for400 microsecond bursts is 0 volts which turns off the MOSFET and letsthe stimulator coil and parallel capacitor resonate for one cycle. Here,the resonance period is 400 microseconds. The stimulator coil Voltage 93(lower trace) has an amplitude of 200 volts. These waveforms match thosepredicted by FIG. 9. Note also that the voltage rises to its maximum inless than 100 microseconds, and this was accomplished with 10 volts DCas the power supply. Hence, it is shown that the coil voltage of 200volts can be much greater than the supply voltage of 10 volts. The pulsegenerator 81 had a repetition rate of 100 cycles per second (not evidentin FIG. 14).

FIG. 15 shows the oscilloscope waveforms of this preferred embodiment ofFIG. 8 using the parts described, but adding a ferromagnetic metal(steel) on the back of the stimulator coil 71. Without limitation, thismetal could also have been iron, cobalt, nickel, or any alloy of thesewith each other or with other metals. Here, the amplitude of theundershoot pulse is now less than half that of the positive sinusoidalpulse. This characteristic of a smaller amplitude of undershoot relativeto the main pulse creates an asymmetric pulse for those stimulationprotocols that specify this shape.

Pulse Shapes

FIG. 16 shows another exemplary simulator coil 1 that is 3.5 inches indiameter with the windings in the outer 0.5 inch periphery, with leadwires 161. A single-turn induction coil 2 was used to measure theinduced voltage produced by the stimulator coil 1. A driver circuit likethe one illustrated in FIG. 8 was connected to stimulator coil 1,including a 0.0047 microfarad parallel capacitor. The white disk is theflange for the top side of the coil's spool. The back perimeter is blacktape to hold the windings inside the outer portion of the spool. Thescrew in the middle reinforces the two flanges of the spool.

FIG. 17 shows the stimulator coil voltage 93 on an oscilloscope alongwith the single-turn induction coil voltage 171. Both signals have aperiod of 130 microseconds on the horizontal time axis. The peak to peakvoltage induced in a full turn 171 was about 2.0 volts, such that 20millivolts would be expected in a 3 mm injectable conductor, as theratio of the injectable length to the induction coil length is 1/100.The 20 millivolts excitation across electrodes spaced by 3 mm is knownto be strong enough to evoke action potentials (the difference betweenthe resting potential of −70 millivolts and the trigger potential −55millivolts is 15 millivolts in FIG. 10) if no myelin exists between theendpoint and the neuron, so this stimulator coil 1 in FIG. 16 andassociated driver circuit is promising for a laboratory demonstration.Note that the stimulation amplitude could be increased by increasing thelength of the injectable conductor proportionately or by increasing thesupply voltage proportionately. In mammals and human beings, the rangeof stimulation voltages required at the injectable is between 10 and 20millivolts if no myelin layer is intervening.

FIG. 18a shows that by doubling the pulse width from the pulsegenerator, two cycles of the resonance can be achieved for stimulationprotocols that benefit from these pulse shapes. In FIG. 18a ,oscilloscope trace 181 is the induced voltage in the single-turnInduction coil and has similar amplitude as that of the single cyclepulses of FIG. 17. The time duration of the two-cycle resonant pulsepair is 260 microseconds.

FIG. 18b shows that the pulse width from the pulse generator can belengthened such that the circuit of FIG. 8 is turned off except when aburst of decaying resonant pulses is needed for stimulation. Trace 93 isthe voltage across the stimulator coil 1 in FIG. 8 and its maximumamplitude is 280 volts and the period of the resonance is 200microseconds. The pulse generator 81 in FIG. 8 is off until Trace 93starts to become negative from the center axis. After turn on, thevoltage is applied to the stimulator coil 1 of FIG. 8 slowly approachesthe supply voltage. Trace 181 in FIG. 18b is the induced voltage in asingle-turn induction coil, and its maximum peak-to-peak voltage is 1.2volts. In FIG. 18b , the pulse generator turns on the circuit of FIG. 8for a time to allow the steady-state current to build up in thestimulator coil. Once this steady state is reached, the pulse generatorturns off the circuit of FIG. 8, and the stimulator coil and capacitorare free to resonate, generating a decaying series of sinusoidal cyclesof trace 93. The lower portion of FIG. 18b shows the bursts of decayingsinusoidal pulses, and the burst rate is 20 bursts per second, or 20 Hz.

The stimulation protocol of FIG. 18b saves energy by not flowing currentin the stimulator coil between bursts. The pulse generator 81 of FIG. 8turns off the stimulator coil except for the 2-millisecond time durationof the build-up of stimulator coil current prior to the resonant burst.After being turned on for 2 milliseconds, the pulse generator keeps thestimulator coil off for 48 milliseconds before repeating the cycle.Hence, the power supply 73 is FIG. 8 is only being tapped 5 percent ofthe time.

FIGS. 19 and 20 show how asymmetric pulse shapes may be generated justby reducing the pulse width of the pulse generator 81 in FIG. 8. InFIGS. 19 and 20, the same hardware was used as in FIGS. 17 and 18 a andthe single-turn induction coil voltage amplitude of Traces 191 and 201was again 2 volts peak to peak and the period was 130 microseconds. FIG.19 shows that an asymmetric pulse shape, wherein the positive portion ofa single sinusoidal period is greater than the negative portion, isachieved when the pulse generator pulse 81 of FIG. 8 width is narrowedto less than one resonant cycle, as illustrated by the single-turninduced coil voltage 191. FIG. 20 shows how a positive-only pulse,wherein the pulse is a positive portion of a sinusoid that is terminatedby turning off the switch before it naturally reaches zero, isachievable by further narrowing the pulse width of the pulse generator.Without limitation, these pulse shapes are available from the drivercircuit when they are desired for the stimulation protocol.

Wearable Coil Designs

FIGS. 21-22 depicted various exemplary configurations of the wearablecoil devices that may be used, generally characterized by flattened coilshapes that are more appropriate to be worn against the skin or on theoutside of the body. The flattened coil shapes may permit the user tocontinue to ambulate and/or his or her daily activities withoutprotruding from substantially from the body, or from underneath theuser's clothing. In some variations, the flattened shape of the wearablecoil device or its housing may have a height relative to the skinsurface that is significantly less than the width and length of thedevice. In some variations, the absolute height of the wearable coildevice is less than 4 cm, 3 cm, 2 cm or 1 cm, for example.

FIGS. 21a and 21b show a flat coil that could be made from either arigid or flexible circuit board. The diameter of the coil and hence thewidth of the circuit board should have the same relationship of 4X theneeded penetration depth, or a circuit board width and height of between1 cm and 40 cm. The rigid material could be the industry standard FR4,or could be glass, or hard plastic with a thickness between 0.5 mm and2.0 mm, with the smaller thickness for smaller diameter coils and thelarger thickness for larger coils. The flexible material could be theindustry standard polyimide, or could be BoPET, polyethylene,polyurethane, nylon or PTFE. The material is selected to achieve theflexibility to follow the contour of the skin, but strong enough to bedurable after multiple applications of the stimulator. The thickness ofthe flexible material is between 12.5 and 200 microns, again dependingon the diameter of the coil that is supported.

In these designs, the windings of the coil on one side are facing thebody, and the injectable is parallel to the windings and as close aspossible to the windings. This portion of the windings facing theinjectable conductor produce a fringing magnetic field that reaches intothe body. These fringing magnetic fields can be made stronger if themagnetic field from the rest of the coil is contained by a material withhigh magnetic permeability. If this material is not electricallyconductive, then it will not lose power from eddy currents within thematerial. Iron and steel are examples of high-permeability materialsthat are electrically conductive. Ferrite, in either flexible or rigidform is an example of a high-permeability material that is notelectrically conductive, and hence a preferred material. Highpermeability materials, both conducting and non-conducting, generallyhave a magnetic permeability that is 10 to 1000 times higher than thatof air, but any material with relative permeability greater than 1 wouldhave a desired effect. The thickness of the high permeability materialshould be between 1 mm and 2 cm depending on a variety of factorsincluding the material's permeability, the weight added to the wearabledevice, and the width and height of the coil.

FIG. 21a shows how a flat high-permeability material 211 can be added tothe back of the coil 1, the side not facing the body, to increase themagnetic field strength and hence provide higher stimulation at theinjectable. Adding this material 211 can also reduce the powerconsumption of the wearable needed for stimulation, especially if it isnot electrically conductive.

FIG. 21b shows how this material 211 can also cover body-facing side ofthe return windings 1 whose adjacent magnetic field is not used forstimulation, further increasing the coil's efficiency. FIGS. 22a and 22bshow another coil 1 configuration that is flattened into a cylindricalshape with an oval cross-section. Here, the windings on one long side ofthe oval faces the body and the injectable conductor, and the returnwindings are on the other long side of the oval, away from the body. Theconfiguration of FIG. 22b similarly uses the high permeability material211 between the body-facing windings and the return windings. The widthand height of the windings should be approximately equal to thepenetration depth to optimize power consumption, hence between 0.25 cmand 10 cm. Because this coil is elongated vs. the round shape of othercoils discussed here, it's form factor is more suitable for some partsof the body like the arms, legs, and extremities.

Animal Study

FIG. 24 shows an apparatus that was used to prove that this NeuralStimulator can stimulate live tissue and cause action potentials tooccur. A mouse brain slice sample 242 was placed under a microscope withobjective lens 241 and the experiment was performed while this brainslice was still alive and active. The stimulator coil 1 was placed 3centimeters from the brain slice with the windings parallel to the brainslice. Lead wires 161 are connected to the same driver circuit used inFIGS. 16-17 Stimulator coil 1 was 7.5 cm in diameter and 1.25 cm thick,and weighed 0.25 pounds, wherein most of the weight was in the coppermagnet wire used for the coil windings.

An injectable conductor 3 made of uninsulated nichrome with diameter 17microns and length 3 mm was placed in the brain slice, as illustrated inthe microscope image of FIG. 25. The magnification of the microscopeimage of FIG. 25 was 10×.

FIG. 26 shows a higher magnification 100× of one endpoint of theinjectable conductor 261. This endpoint is the target location for thestimulation to occur. An action potential sensor 262 was placed onanother neuron cell about 200 microns away from the injectable endpoint261. This sensor was used in the experiment to detect action potentialscreated by the Neural Stimulator's stimulation effect. FIG. 27 shows thestimulator coil voltage 271 on the oscilloscope, with a biphasic,charge-neutral, sinusoidal pulse shape. The repetition rate of burst is104.4 Hz from the pulse generator 272 frequency. The amplitude of thecoil 1 voltage was 1600 volts, and the period of the sinusoidalbi-phasic pulse was 130 microseconds. The power consumption of thestimulator coil and the driver circuit was 14 watts. In thisdemonstration, the stimulator coil was not turned off betweenstimulation bursts.

When the stimulator is not active, the sensor output is negative 62millivolts, which is typical for a live mouse neuron resting potential281 in FIG. 28. When the stimulator is turned on, a steady stream ofstimulated action potentials 291 is evident in the nearby neuron by theoutput of the action potential sensor 262 in FIG. 26. The other, morefrequent, pulses in the trace of FIG. 29 represent electromagneticinterference from the stimulator coil. Hence, the Neural Stimulator andits reduction to practice, as described, is effective in stimulating atargeted location in the brain, and this stimulation causes actionpotentials downstream in the neuronal network.

Wearable Housing

The wearable portion of this device contains at least the stimulatorcoil, which is facing the body and positioned as close as possible tothe injectable conductor. The battery and driver circuit may be combinedwith the stimulator coil into one unit or these may be carriedseparately in a more convenient location. In most designs, the drivercircuit fits into the center hole of the spool containing the windingsof the simulator coil. This assembly is fully enclosed in a hard orpartially flexible plastic housing. The thickness of the housing shouldbe as thin as possible to minimize the distance from the coil windingsto the injectable, but thick enough to be strong and uncompromised whendropped or after normal use or normal misuse. The housing must protectthe user and others who handle it from the voltages generated inside. Acontact sensor can turn the system off when not placed against the skinto save battery life and to prevent physical vibration of nearbyferromagnetic objects.

The coil and driver circuit assembly should be mounted snugly againstthe body using the aforementioned attachment methods, as the stimulationintensity will vary with the distance between the injectable and thecoil windings. If the battery is not contained in this assembly, thenwires are routed to the battery's location to bring power to the coiland driver circuit assembly.

Injection System and Method

FIG. 23 illustrates the injectable being placed by a syringe. Theinjectable conductor 3 passes through a syringe 231 with a hollow needle234 to the appropriate position to be stimulated. First, the injectableconductor 3 is placed in the hollow needle 234 of the syringe 231, asillustrated in FIGS. 23a and 23b . Second, a longer cylinder 232 such asnylon thread, preferably non-conducting, of similar diameter pushes theinjectable conductor through the needle until the injectable 3 is nearthe end of the needle. The placement of the conductor into the body isillustrated in FIGS. 23c to 23f . The needle 234 is inserted into thebody 235, guided by an X-ray, fluoroscopy, CT, MRI, ultrasound,endoscopy or other real-time imaging system, until the tip of the needleis at the stimulation location 40. For example, B-mode ultrasoundimaging may be employed with the imaging probe located to the left orright side of the body 235. Such a configuration would display an imageof the cross-sectional plane that contains both the syringe needle andthe ultimate placement of the injectable as well as a cross section ofthe nerve 40, enabling the surgeon or physician to place the injectableaccurately. Then, a hand or mechanical gripper pushes the plunger 233 inFIG. 23a of the syringe 231, which pushes the injectable out of theneedle. Once the injectable is pushed to the desired location near, thecylinder 232 in FIG. 23a is backed out by the gripper, and then theentire syringe 231 is backed out, leaving the injectable in place. Insome embodiments where the injectable needs to be stimulated and thestimulation response observed to help guide the injectable to the targetlocation, the wearable portion could be mounted nearby and activatedduring the injection. Without limitation, the needle could be preloadedwith one or more injectable conductors and each one placed sequentiallyinto nearby locations, and the injectable system be part of a kit anddelivered in a sealed and sterile package.

Wearable Installation and Calibration

Once the injectable conductor is in the appropriate location, thewearable portion is mounted as it will be worn by the patient. Theintensity of the stimulation is increased by slowly increasing thevoltage to the driver circuit. When the desired amount of stimulation isachieved, that voltage level is noted by the controller portion of thedriver circuit. If appropriate, the attending physician will thenspecify a range of voltages around this level that the patient is ableto set without supervision. If not appropriate, the patient will have astimulation that was fixed by the physician, and cannot be changedwithout the physician present. If the patient does have ability tochange the stimulation parameters, these can be accomplished through asmart phone or similar interface. Without limitation, the patient orattending physician could also have the liberty of adjusting the burstfrequency, pulse shape, burst duration, pulse duration, and/or otherparameter instead of or in addition to the voltage level. The desiredamount of stimulation or other parameter could, depending on the natureof the treatment and the ability of the patient, be determined byfeedback from patient or calibrated to a reference level based onfeedback from other electrical signals in the body such as EKG, EMG, orother signal, or to another reference level pre-determined to beeffective in a clinical trial. For example, EMG signals from healthy andconnected muscles could be used to recruit and stimulate nervesconnecting other muscles in the same muscle group that are unconnecteddue to pathology or injury. Another example is in prosthesis wherein thenerve is damaged, and the upstream nerve signals are used to triggerstimulation in the healthy downstream portion of the nerve. In themanagement of high blood pressure and heart rate the EKG or othersignals could be used to trigger the stimulator to depolarize theneurons in the brain that create a sense of anxiety, thereby relaxingthe entire neurological system.

Temporary and Permanent Installation

The methods just described can allow the patient to experience life withthe Neural Stimulator active for a trial period, if desired. After thetrial period, the patient and the attending physician will determine ifthe Neural Stimulator should be adjusted, terminated, or the injectablerepositioned. Stimulation parameter adjustments can be made by re-usingthe feedback methods described for initial settings. If termination isdesired, then the patient can likely continue a normal life with theinjectable conductor in its current location, but not activate it withthe wearable portion. The inactivated injectable conductor is notexpected to cause complications in normal living or during MRI, X-ray,or other normal diagnostic procedure. If the injectable conductor iscausing complications or the patient or physician wants it removed foranother reason, then it can be removed using methods and tools that areused for a biopsy or removing cancerous tissue, such as keyhole surgery,guided by imaging such as functional MRI and/or ultrasound. If theinjectable conductor needs to be repositioned, then another one could beplaced downstream along the nerve pathway of the nerve to be stimulated,leaving the first injectable conductor in place. Or, the firstinjectable conductor may be removed and another one injected.

As noted previously, the driver circuit 4 in FIG. 1A may comprise aprocessing device, as schematically depicted in FIG. 30, which in turnmay comprise a controller connected to one or more stimulation coils 1.The controller may comprise one or more processors 301 and one or moremachine-readable memories 302 in communication with the one or moreprocessors. The processor may incorporate data received from memory andoperator input 304 to control the processing device. The inputs to thecontroller may be received from one or more machine generated and/orhuman generated sources (e.g., user input). The memory 302 may furtherstore instructions to cause the processor 301 to execute modules,processes and/or functions associated with the processing device, suchas the method steps described herein. The processor, memory, andinterfaces may be local to the wearable device 7 or at a remotecomputing facility 307 in communication with the wearable 7 over anetwork interface 306.

The controller may be implemented consistent with numerous generalpurpose or special purpose computing systems or configurations. Variousexemplary computing systems, environments, and/or configurations thatmay be suitable for use with the systems and devices disclosed hereinmay include, but are not limited to software or other components withinor embodied on personal computing devices, network appliances, servers,or server computing devices such as routing/connectivity components,portable (e.g., hand-held) or laptop devices, multiprocessor systems,microprocessor-based systems, and distributed computing networks.Examples of portable computing devices include smartphones, personaldigital assistants (PDAs), cell phones, tablet PCs, phablets (personalcomputing devices that are larger than a smartphone, but smaller than atablet), wearable computers taking the form of smartwatches, portablemusic devices, and the like, and portable or wearable augmented realitydevices that interface with an operator's environment through sensorsand may use head-mounted displays for visualization, eye gaze tracking,and user input.

Processor

The processor may be any suitable processing device configured to runand/or execute a set of instructions or code and may include one or moredata processors, image processors, graphics processing units, physicsprocessing units, digital signal processors, and/or central processingunits. The processor 301 in FIG. 30 may be, for example, ageneral-purpose processor, Field Programmable Gate Array (FPGA), anApplication Specific Integrated Circuit (ASIC), and the like. Theprocessor may be configured to run and/or execute application processesand/or other modules, processes and/or functions associated with thesystem and/or a network associated therewith. The underlying devicetechnologies may be provided in a variety of component types, e.g.,metal-oxide semiconductor field-effect transistor (MOSFET) technologieslike complementary metal-oxide semiconductor (CMOS), bipolartechnologies like emitter-coupled logic (ECL), polymer technologies(e.g., silicon-conjugated polymer and metal-conjugated polymer-metalstructures), mixed analog and digital, and the like.

Memory

In some variations, the memory 302 in FIG. 30 may include a database(not shown) and may be, for example, a random access memory (RAM), amemory buffer, a hard drive, an erasable programmable read-only memory(EPROM), an electrically erasable read-only memory (EEPROM), a read-onlymemory (ROM), Flash memory, and the like. As used herein, databaserefers to a data storage resource. The memory may store instructions tocause the processor to execute modules, processes and/or functionsassociated with the processing device (108), such as ECG signal dataprocessing, communication, display, and/or user settings. In somevariations, storage may be network-based as shown by 303 within theRemote Portion 307 in FIG. 30 and accessible for one or more authorizedusers. Network-based storage may be referred to as remote data storageor cloud data storage. Historical usage or physiological signal datastored in cloud data storage (e.g., database) may be accessible torespective users via a network, such as the Internet. In somevariations, database may be a cloud-based FPGA.

Some variations described herein relate to a computer storage productwith a non-transitory computer-readable medium (also may be referred toas a non-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals per se (e.g., a propagating electromagnetic wavecarrying information on a transmission medium such as space or a cable).The media and computer code (also may be referred to as code oralgorithm) may be those designed and constructed for a specific purposeor purposes. Examples of non-transitory computer-readable media include,but are not limited to, magnetic storage media such as hard disks;optical storage media; holographic devices; magneto-optical storagemedia such as optical disks; solid state storage devices such as a solidstate drive (SSD) and a solid state hybrid drive (SSHD); carrier wavesignal processing modules; and hardware devices that are speciallyconfigured to store and execute program code, such asApplication-Specific Integrated Circuits (ASICs), Programmable LogicDevices (PLDs), Read-Only Memory (ROM), and Random-Access Memory (RAM)devices. Other variations described herein relate to a computer programproduct, which may include, for example, the instructions and/orcomputer code disclosed herein.

The systems, devices, and/or methods described herein may be performedby software (executed on hardware), hardware, or a combination thereof.Hardware modules may include, for example, a general-purpose processor(or microprocessor or microcontroller), a field programmable gate array(FPGA), and/or an application specific integrated circuit (ASIC).Software modules (executed on hardware) may be expressed in a variety ofsoftware languages (e.g., computer code), including C, C++, JAVA®,Python, Ruby, VISUAL BASIC®, and/or other object-oriented, procedural,or other programming language and development tools. Examples ofcomputer code include, but are not limited to, micro-code ormicro-instructions, machine instructions, such as produced by acompiler, code used to produce a web service, and files containinghigher-level instructions that are executed by a computer using aninterpreter. Additional examples of computer code include, but are notlimited to, control signals, encrypted code, and compressed code.

User Interface

A user interface may permit an operator to interact with and/or controlthe processing device directly and/or remotely. For example, the userinterface may include an input device like 304 in FIG. 30 for anoperator to input commands and an output device like 305 in FIG. 30 foran operator and/or other observers to receive output (e.g., view patientdata on a display device) related to operation of the processing device.

User interface may serve as a communication interface between anoperator and the processing device 301. In some variations, the userinterface may comprise an input device 304 and output device 305 (e.g.,touch screen and display) and be configured to receive input data andoutput data from one or more of the wearable portions 7, computingdevices 301, input device 304, and output device 305. For example,physiological signal data generated by another device may be processedby processors 301 within wearable portion 7 or remote portion 307 anddisplayed by the output device 305 (e.g., monitor display). As anotherexample, operator control of an input device 304 (e.g., joystick,keyboard, touch screen) may be received by user interface and thenprocessed by controller 7 or 307 for user interface to output a controlsignal to one or more of the processing device 301.

Output Device

An output device 305 in FIG. 30 of a user interface may outputhistorical or physiological signal data corresponding to a user, and maycomprise one or more of a display device and audio device. The displaydevice may be configured to display a graphical user interface (GUI). Adisplay device 305 may permit an operator to view a physiological signaldata and/or other data processed by the controller 7 or 307 or otherdevice (not shown). In some variations, an output device 305 maycomprise a display device including one or more of a light emittingdiode (LED), liquid crystal display (LCD), electroluminescent display(ELD), plasma display panel (PDP), thin film transistor (TFT), organiclight emitting diodes (OLED), electronic paper/e-ink display, laserdisplay, and holographic display.

An audio device may audibly output subject data, sensor data, systemdata, alarms and/or warnings. In some variations, an audio device maycomprise at least one of a speaker, piezoelectric audio device,magnetostrictive speaker, and/or digital speaker. In some variations, anoperator may communicate with other users using the audio device and acommunication channel. For example, the operator may form an audiocommunication channel (e.g., VoIP call) with a remote operator,technician, and/or subject.

Input Device

Some variations of an input device 304 in FIG. 30 may comprise at leastone switch configured to generate a control signal. For example, aninput device may comprise a touch surface for an operator to provideinput (e.g., finger contact to the touch surface) corresponding to acontrol signal. An input device comprising a touch surface may beconfigured to detect contact and movement on the touch surface using anyof a plurality of touch sensitivity technologies including capacitive,resistive, infrared, optical imaging, dispersive signal, acoustic pulserecognition, and surface acoustic wave technologies. In variations of aninput device comprising at least one switch, a switch may comprise, forexample, at least one of a button (e.g., hard key, soft key), touchsurface, keyboard, analog stick (e.g., joystick), directional pad,pointing device (e.g., mouse), trackball, jog dial, step switch, rockerswitch, pointer device (e.g., stylus), motion sensor, image sensor, andmicrophone. A motion sensor may receive operator movement data from anoptical sensor and classify an operator gesture as a control signal. Amicrophone may receive audio and recognize an operator voice as acontrol signal.

Network Interface

As depicted in FIG. 30, a processing device described herein maycommunicate with one or more networks and computing devices through anetwork interface 306. In some variations, the processing device may bein communication with other devices via one or more wired and/orwireless networks. For example, the network interface 306 may permit theprocessing device 301 in wearable portion 7 to communicate with one ormore of a network 306 (e.g., Internet), remote server, and database. Thenetwork interface 306 may facilitate communication with other devicesover one or more external ports (e.g., Universal Serial Bus (USB),multi-pin connector) configured to couple directly to other devices orindirectly over a network (e.g., the Internet, wireless LAN).

In some variations, the network interface 306 may compriseradiofrequency (RF) circuitry (e.g., RF transceiver) including one ormore of a receiver, transmitter, and/or optical (e.g., infrared)receiver and transmitter configured to communicate with one or moredevices and/or networks. RF circuitry may receive and transmit RFsignals (e.g., electromagnetic signals). The RF circuitry convertselectrical signals to/from electromagnetic signals and communicates withcommunications networks and other communications devices via theelectromagnetic signals. The RF circuitry may include one or more of anantenna system, an RF transceiver, one or more amplifiers, a tuner, oneor more oscillators, a digital signal processor, a CODEC chipset, asubscriber identity module (SIM) card, memory, and the like. A wirelessnetwork may refer to any type of digital network that is not connectedby cables of any kind. Examples of wireless communication in a wirelessnetwork include, but are not limited to cellular, radio, satellite, andmicrowave communication. The wireless communication may use any of aplurality of communications standards, protocols and technologies,including but not limited to Global System for Mobile Communications(GSM), Enhanced Data GSM Environment (EDGE), high-speed downlink packetaccess (HSDPA), wideband code division multiple access (W-CDMA), codedivision multiple access (CDMA), time division multiple access (TDMA),Bluetooth, Wireless Fidelity (Wi-Fi) (e.g., IEEE 802.11a, IEEE 802.11b,IEEE 802.11g and/or IEEE 802.11n), voice over Internet Protocol (VoIP),Wi-MAX, a protocol for email (e.g., Internet Message Access Protocol(IMAP) and/or Post Office Protocol (POP)), instant messaging (e.g.,eXtensible Messaging and Presence Protocol (XMPP), Session InitiationProtocol for Instant Messaging and Presence Leveraging Extensions(SIMPLE), and/or Instant Messaging and Presence Service (IMPS)), and/orShort Message Service (SMS), or any other suitable communicationprotocol. Some wireless network deployments combine networks frommultiple cellular networks or use a mix of cellular, Wi-Fi, andsatellite communication. In some variations, a wireless network mayconnect to a wired network in order to interface with the Internet,other carrier voice and data networks, business networks, and personalnetworks. A wired network is typically carried over copper twisted pair,coaxial cable, and/or fiber optic cables. There are many different typesof wired networks including wide area networks (WAN), metropolitan areanetworks (MAN), local area networks (LAN), Internet area networks (IAN),campus area networks (CAN), global area networks (GAN), like theInternet, and virtual private networks (VPN). As used herein, networkrefers to any combination of wireless, wired, public, and private datanetworks that are typically interconnected through the Internet, toprovide a unified networking and information access system.

Software Architecture

FIGS. 31a and 31b show the software architecture of the wearable portionof this Neural Stimulator. Two modes of operation are shown. FIG. 31ashows the mode of operation wherein power is saved by turning the systemoff in between bursts, which generates the fully and naturally decayingresonance bursts shown in FIG. 18b . FIG. 31b shows a mode of operationwherein the resonance is terminated after a number of resonant cycles,which could include fractional cycles, which generates the pulse shapesshown in FIGS. 15, 16, 18 a, 19 and 20.

In FIG. 31a , the stimulation protocol determines the two parameters ofthe stimulator that are not hardware dependent in the embodiments shownthus far, and these parameters are the pulse amplitude and the burstinterval, which designates the elapsed time between bursts ofstimulation pulses. The pulse amplitude designated by the stimulationprotocol sets the power supply 73 voltage, which is assumed to beprogrammable. The relationship between the supply voltage and the pulseamplitude generated at the injectable site is pre-determined duringcalibration of the system prior to injection in a simulated environment.This relationship is stored as a lookup table in the Memory 302 of theWearable Portion 7 in FIG. 30. The stimulation protocol also designatesthe Burst Interval BI, which sets the periodicity of the switching ofthe Driver Circuit 4. In the power saving mode of operation, all powerto the coil is turned in between bursts of pulses. Because of theinductance of the stimulator coil, the driver circuit must be turned onsufficiently prior to the burst to allow needed current to build up inthe coil. The time needed for this buildup (BU) is related to the timeconstant L/R, wherein L is the inductance of the coil and R is theresistance of the coil plus any other resistances in the path from thepower supply to ground. As illustrated in FIG. 31a , the coil is turnedon for enough time for current to build up, which is the build-up timeBU. Then, the stimulator is turned off, allowing the stimulator coil 1and the parallel capacitor to resonate, generating a decaying series ofbi-phasic sinusoidal pulses as illustrated in FIG. 18. The stimulatorstays off until it is time to start building up the current in the coilagain prior to the next burst, which is BI minus BU seconds.

FIG. 31b illustrates a different mode of operation, which consumes morepower than the operation in FIG. 31a , but allows for more flexibilityin pulse shapes, including the mono-phasic pulse shape illustrated inFIG. 20. The pulse amplitude is determined and set the same as wasdescribed for FIG. 30a . In this mode, the stimulator coil is normallyturned on with full current flowing, even in between bursts. The steadycurrent between bursts maintains a zero voltage at the injectablebecause the induced voltage, by Faraday's law, is the time derivative ofthe magnetic field, which is proportional to the coil current. When aburst is needed, the stimulator coil is turned off and is allowed it toresonate with the parallel capacitor for RI seconds, as the stimulationprotocol designates. The stimulator in this case generates single ormultiple periods of biphasic sinusoidal pulses or fractions thereof, asillustrated in FIG. 15, 16, 18 a, 19 or 20. Once the resonance isstopped by the turning the stimulator coil back on after RI seconds, thecontroller waits until the next burst is required, which is the burstinterval BI minus the resonance interval RI.

Although the present disclosure has been described in relation tovarious exemplary embodiments, various additional embodiments andalterations to the described embodiments are contemplated within thescope of the disclosure. Thus, no part of the foregoing descriptionshould be interpreted to limit the scope of the invention as set forthin the following claims. For all of the embodiments described above, thesteps of the methods need not be performed sequentially.

I claim:
 1. A neuromodulation system, comprising: one or more injectablemicrostimulators comprising a length of 10 mm or less, a diameterbetween 0.5 mm and 3 mm, and lacking a battery; and a free runningresonance magnetic field generator, comprising: a coil: a capacitorconnected in parallel with the coil such that a stimulation signal is aportion in time of a resonance between the parallel capacitor and coil;a DC power supply at a first side of the parallel capacitor and coil,and configured to activate the parallel coil and capacitor; and a switchto ground on a second side of the parallel capacitor and coil, whereinthe switch comprises a transistor and a rectifier; wherein the switch isconfigured to turn off a gate or a base of the transistor just prior toa first series of decaying resonant pulses to provide a free runningresonance between the coil and the capacitor and then turn on to buildup a current in the magnetic field generator prior to a second series ofdecaying resonant pulses to reduce electrical energy in the coil betweenthe first and second series.
 2. The neuromodulation system of claim 1,wherein the switch is configured to open at a beginning of a first fullresonant cycle and to close at one of: prior an end of the first fullresonant cycle; at the end of the first full resonant cycle; at the endof a later resonant cycle; or within a later resonant cycle.
 3. Theneuromodulation system of claim 1, wherein the magnetic field generatorfurther comprises an H driver with four switches that are configured toactivate the parallel capacitor and coil.
 4. The neuromodulation systemof claim 3, wherein a first two of the four switches are configured toopen and a second two of the four switches are configured to close atthe beginning of a first half of a resonant cycle; and wherein the firsttwo of the four switches are configured to close and the second two ofthe four switches are configured to open at the end of as second half ofthe resonant cycle.
 5. The neuromodulation system of claim 1, whereinthe DC power supply is configured to provide an output voltage of 3 to45 volts.
 6. The neuromodulation system of claim 1, wherein eachmicrostimulator comprises a monolithic body.
 7. The neuromodulationsystem of claim 1, wherein each microstimulator consists a wire segmentwith exposed ends and a central wire coating.
 8. The neuromodulationsystem of claim 1, wherein the one or more microstimulators are locatedin an injection device comprising a needle.
 9. The neuromodulationsystem of claim 1, wherein the magnetic field generator furthercomprises one or more of a microprocessor, rechargeable battery, userinterface, data storage and a network interface.
 10. The neuromodulationsystem of claim 1, wherein magnetic field generator is configured togenerate a current of 10 to 50 microamps and 20 to 200 millivolts in theinjectable microstimulator.
 11. The neuromodulation system of claim 1,wherein the magnetic field generator is configured to generate anelectric field strength between 1.0 and 100 volts/meter at theinjectable microstimulator location.
 12. The neuromodulation system ofclaim 1, wherein the magnetic field generator further comprise a housingwith a skin contact surface and a height from the skin contact surfacethat is less than 1 cm.
 13. The neuromodulation system of claim 12,wherein the coil is a flexible coil located on a flexible circuit board.14. The neuromodulation system of claim 13 wherein magnetic fieldgenerator is configured to contour to a skin surface and furthercomprises a flexible strap configured to releasably attach the housingto a body region of a patient.
 15. The neuromodulation system of claim12, wherein the magnetic field generator is selected with a coildiameter that is on the order of 4 times a distance from the skinsurface of the housing to an implant location of the one or moremicrostimulators.
 16. The neuromodulation system of claim 1, wherein themagnetic field generator is configured during therapy to use 100 peakamps or less.